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08:47
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Mitochondrion-dependent caspase activation by the HIV-1 envelope
Thomas Roumier1, Maria Castedo, Jean-Luc Perfettini
1Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Biochemical Pharmacology
|October 14, 2003
Summary
Human immunodeficiency virus envelope glycoproteins induce cell fusion, leading to apoptosis. This study reveals that HIV-induced syncytial apoptosis involves the intrinsic mitochondrial pathway, regulated by caspase activation.
Area of Science:
- Cell Biology
- Virology
- Immunology
Background:
- Human immunodeficiency virus (HIV) envelope glycoproteins (Env) mediate cell fusion with CD4+ and CXCR4+ cells.
- This fusion process results in the formation of syncytia, which subsequently undergo apoptosis (programmed cell death).
Purpose of the Study:
- To develop and utilize a cytofluorometric assay for quantifying syncytium formation and syncytial apoptosis.
- To investigate the molecular mechanisms underlying Env-elicited syncytial apoptosis, focusing on caspase activation and mitochondrial pathways.
Main Methods:
- Development of a novel cytofluorometric assay to measure syncytium formation and apoptosis.
- Pharmacological and genetic interventions targeting cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP).
- Transfection with viral mitochondrial inhibitors of apoptosis and assessment of caspase-3 activation and cytochrome c release.
Main Results:
- Caspase activation in syncytia was inhibited by interventions targeting cyclin-dependent kinase-1, p53, and MMP.
- Inhibition of MMP using a cytomegalovirus-encoded viral mitochondrial inhibitor prevented cytochrome c release and abolished caspase-3 activation.
- Conversely, caspase inhibition did not prevent MMP, indicating MMP precedes caspase activation.
Conclusions:
- Env-elicited syncytial apoptosis is primarily mediated by the intrinsic (mitochondrial) apoptotic pathway.
- Mitochondrial membrane permeabilization is a critical upstream event in HIV-induced syncytial apoptosis.
- Targeting the mitochondrial pathway offers potential therapeutic strategies against HIV-induced cell death.
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